This is a 371 of PCT/JP98/02885, filed Jun. 26, 1998.
The present invention relates to novel benzimidazole derivatives, and, more precisely, to novel benzimidazole derivatives and their pharmaceutically acceptable salts having blood sugar level-depressing activity or PDE5-inhibiting activity. The present invention also relates to pharmaceutical compositions comprising, as an active ingredient, such benzimidazole derivatives or their salts.
The subject matter of the present invention is to provide novel benzimidazole derivatives and their pharmaceutically acceptable salts, and also pharmaceutical compositions which comprise, as an active ingredient, such benzimidazole derivatives or their pharmaceutically acceptable salts, and which are useful for preventing and treating impaired glucose tolerance, diabetes (type II diabetes), diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc.), syndrome of insulin resistance (e.g., insulin receptor disorders, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly, etc.), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.), hyperglycemia (e.g., abnormal saccharometabolism such as feeding disorders, etc.), hypertension, stenocardia, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g., renopathy induced by FK506, cyclosporin, etc.), renal failure, atherosclerosis aiiostenosis (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chrci reversible obstructions (e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.), autoimmune disease, allergic rhinitis, urticaria, glaucoma, diseases characterized by enteromotility disorders (e.g., hypersensitive enteropathy syndrome, etc.), impotence (e.g., organic impotence, psychic impotence, etc.), nephritis, cachexia (e.g., progressive weight loss due to the lipolysis, myolysis, anemia, edema, anorexia, etc. associated with chronic diseases such as cancer, tuberculosis, endocrine disorder, AIDS, etc.), pancreatitis, or restenosis after PTCA.
The present inventors provide a novel benzimidazole derivative represented by the following formula (I) and its pharmaceutically acceptable salt, and a pharmaceutical composition comprising said compound or its pharmaceutically acceptable salt as an effective ingredient, which is usable for preventing and treating impaired glucose tolerance, diabetes (type II diabetes), diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc.), syndrome of insulin resistance (e.g., insulin receptor disorders, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly, etc.), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.), hyperglycemia(e.g., abnormal saccharometabolism such as feeding disorders, etc.), hypertension, stenocardia, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g., renopathy induced by FK506, cyclosporin, etc.), renal failure, atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chronic reversible obstructions (e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.), autoimmune disease, allergic rhinitis, urticaria, glaucoma, diseases characterized by enteromotility disorders (e.g., hypersensitive enteropathy syndrome, etc.), impotence (e.g., organic impotence, psychic impotence, etc.), and nephritis, cachexia (e.g., progressive weight loss due to the lipolysis, myolysis, anemia, edema, anorexia, etc. associated with chronic diseases such as cancer, tuberculosis, endocrine disorder, AIDS, etc.), pancreatitis, or restenosis after PTCA. 
wherein R1 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a lower alkylthio group;
R2 represents an aromatic lower alkyl group, which may be substituted with one or more groups selected from a halogen atom, an alkyl group, a halo-lower alkyl group, a nitro group, a lower alkoxycarbonyl group, an aromatic group, an aromatic lower alkyloxy group, a lower cycloalkyloxy-lower alkyl group, an aromatic lower alkyl group, an aromatic lower alkenyl group, an aromatic lower alkynyl group, an aromatic oxy lower alkyl group, a lower cycloalkyl-lower alkyloxy group, an alkenyl group, a lower alkoxy group, a lower alkylthio group, a lower alkanesulfinyl group, a lower alkanesulfonyl group, and a lower alkanesulfonylcarbamoyl group;
R3 represents an alkyl group, a hydroxy lower alkyl group, an alkenyl group, an aromatic group, a halogenated aromatic group, a lower alkyl aromatic group, a lower alkenyl aromatic group, an aromatic lower alkyl group, or an aromatic lower alkenyl group; and xe2x80x94Xxe2x80x94 is a cross-linking group represented by any one of the following formulas (II) to (VI): 
In the above formula (I), R1 is preferably a lower alkyl group, and X is a cross-linking group represented by the above formula (V).
The benzimidazole derivatives provided by the present invention can be prepared according to the following reaction formulae (a) to (m). 
wherein R1, R2, and R3 have the same meanings as described above, R is a protecting group for a carboxyl group, and Z is a halogen atom.
Compound (1) can be converted to Compound (2) by hydrolyzing it with a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. (Reaction formula (a)). Compound (3) can be obtained by treating Compound (2) with a carboxylic acid activator represented by N,Nxe2x80x2-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a salt thereof, dicyclohexylcarbodiimide, isobutyloxycarbonyl chloride, isobutyloyl chloride, pivaloyl chloride, isobutyl chloroformate, diphenylphosphoryl azide, or diethyl cyanophosphate followed by reacting with the corresponding sulfonamide in the presence of a base represented by diazabicycloundecene, triethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, pyridine, N-methylmorpholine, N-ethylpiperidine, potassium hydroxide, sodium hydroxide, potassium phosphate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, sodium hydride, potassium t-butoxide, sodium methoxide, or sodium ethoxide (Reaction formula (b)) The compound obtained by the reaction between Compound (2) and the carboxylic acid activator may or may not be isolated.
Compound (6) can be obtained by reacting Compound (2) with an aminosulfonamide in the presence of carbonyldiimidazole, etc. (Reaction formula (g)).
Compound (7) can be obtained by reacting Compound (2) with hydrazine with one of the amino groups thereof protected in the presence of carbonyldiimidazole, etc. and treating the resulting product under the acidic conditions (Reaction formula (h)). Compound (7) can be converted to Compound (8) by reacting it with sulfonyl chloride or the like in the presence of a base such as triethylamine, etc. (Reaction formula (i)).
Compound (2) can be converted to Compound (9) by reacting it with diphenylphosphoryl azide and an alcohol in the presence of a base such as triethylamine, etc. (Reaction formula (j)). Compound (9) can be converted to Compound (10) by treating it under acidic conditions (Reaction formula (k)). Compound (10) can be converted to Compound (11) by reacting it with sulfonyl isocyanate (Reaction formula (1)), and to Compound (12) with isocyanate (Reaction formula (m)), respectively.
The terms xe2x80x9csulfonamides,xe2x80x9d xe2x80x9caminosulfonamides,xe2x80x9d xe2x80x9csulfonyl chlorides,xe2x80x9d xe2x80x9csulfonyl isocyanates,xe2x80x9d and xe2x80x9cisocyanatesxe2x80x9d used herein mean those groups having the above-described substituent R3, where a functional group, if present on the carbon atom thereof, may or may not be protected. Compound (3) having the protected functional group can be converted to the desired compound by deprotection.
Compound (2) can be converted to the corresponding acid halide represented by Compound (4) by reacting it with thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, or phosphorus tribromide, etc. (Reaction formula (c)). Compound (3) can be synthesized from Compound (4) and sulfonamide in the presence or absence of a base (Reaction formula (d)).
Compound (5) can be synthesized by reacting Compound (4) with ammonia or ammonia water (Reaction formula (e)). Compound (5) can also be synthesized from Compound (1) and ammonia or ammonia water. Alternatively, Compound (5) can be obtained by reacting an intermediate that is produced from Compound (2) and the carboxylic acid activator in the Reaction formula (b) with ammonia or ammonia water. Compound (3) can also be synthesized from Compound (5) and sulfonyl chloride in the presence or absence of a base (Reaction formula (f)).
When R1, R2, or R3 has a reactive substituent in any of the compounds of Compound (1) to Compound (12), the substituent can be replaced to the other during the steps of (a) to (m) or in the final step.
If desired, the intermediates formed in the above-mentioned steps may optionally be purified, prior to being subjected to the next step, through any conventional purification including, for example, recrystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography and the like. If also desired, the final products of the compounds of the present invention may optionally be purified through any conventional purification which is employed in the art of purifying organic compounds and which includes, for example, recrystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography and the like. To identify these compounds, employable is any of NMR spectrography, mass spectrography, IR spectrography, elementary analysis, measurement of melting point and others.
Preferred Examples and their details of various definitions as referred to herein to be within the scope of the present invention are described below.
The alkyl group used herein means a linear or branched alkyl group having 1 to 20 carbon atoms, including a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, an i-pentyl group, a sec-pentyl group, a 2,2-dimethylpentyl group, a 2-methylbutyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethyl-butyl group, a 3,3-dimethylbutyl group, a 1-ethyl-1-methylpropyl group, an n-heptyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a 5-methyl-hexyl group, a 1-ethylpentyl group, a 2-ethylpentyl group, a 1,1-dimethylpentyl group, a 2,2-dimethylpentyl group, a 3,3-dimethylpentyl group, an n-octyl group, a 1-methylheptyl group, a 2-methylheptyl group, a 3-methylheptyl group, a 4-methylheptyl group, a 5-methylheptyl group, a 6-methylheptyl group, a 1-ethylhexyl group, a 2-ethylhexyl group, a 1,1-dimethylhexyl group, a 2,2-dimethylhexyl group, a 3,3-dimethylhexyl group, a n-nonyl group, a 1-methyloctyl group, a 2-methyloctyl group, a 3-methyloctyl group, a 4-methyloctyl group, a 5-methyloctyl group, a 6-methyloctyl group, a 7-methyloctyl group, a 1-ethyl-heptyl group, a 2-ethyl heptyl group, a 1,1-dimethylheptyl group, a 2,2-dimethylheptyl group, a 3,3-dimethylheptyl group, an n-decyl group, a 1-methylnonyl group, a 2-methylnonyl group, a 3-methylnonyl group, a 4-methylnonyl group, a 1-ethyloctyl group, a 2-ethyloctyl group, an n-undecyl group, an n-dodecyl group, an n-tridecyl group, an n-tetradecyl group, an n-pentadecyl group, an n-hexadecyl group, an n-octadecyl group, etc. Preferably, those having 2 to 8 carbon atoms are used.
The term xe2x80x9clowerxe2x80x9d means the number of carbon atoms from 1 to 6. Preferable examples of the lower alkyl group include a straight chain or branched chain alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, 2-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-1-methylpropyl, or the like. Those having carbon atoms of 1 to 3 are more preferred.
The term xe2x80x9chydroxy lower alkyl groupxe2x80x9d means the above-described lower alkyl group to which a hydroxyl group is bonded, including 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl. 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 1-hydroxylhexyl, 2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 6-hydroxylhexyl, 3,4-dihydroxybutyl, 2,4-dihydroxypentyl, 1,3,5-trihydroxyhexyl, (2-hydroxy-1-methyl)ethyl, (1-hydroxy-2-methyl)propyl, (2-hydroxy-2-mnethyl)propyl, (2-hydroxymethyl)propyl, (3-hydroxy-1-methyl)propyl, (4-hydroxy-1-methyl)butyl, (1-hydroxy-3-methyl)-butyl, (2-hydroxy-3-methyl)butyl, (3-hydroxy-3-methyl)butyl, (3-hydroxymethyl)butyl, (1-hydroxy methyl)pentyl, (2-hydroxy-4-methyl)pentyl, (3-hydroxy-4-methyl)pentyl, (4-hydroxy-4-methyl)-pentyl, (4-hydroxymethyl)pentyl, (1,1-dimethyl-2-hydroxy)ethyl, (1,1-dimethyl-2-hydroxy)propyl, (1,1-dimethyl-3-hydroxy)propyl, (1,1-dimethyl-2-hydroxy)butyl, (1,1-dimethyl-3-hydroxy)butyl, (1,1-dimethyl-4-hydroxy)butyl, (1-hydroxy-1-methyl)butyl, (2,2-dimethyl-1-hydroxy)butyl, (2,2-dimethyl-3-hydroxy)butyl, (2,2-dimethyl-4-hydroxy)butyl, (2-hydroxymethyl-2-methyl)butyl, (3,3-dimethyl-1-hydroxy)butyl, (3,3-dimethyl-2-hydroxy)butyl, (3,3-dimethyl-4-hydroxy)butyl, (3-hydroxymethyl-3-methyl)butyl, etc.
The alkenyl group used herein means a linear or branched alkenyl group having 2 to 20 carbon atoms, including a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1-methyl-1-propenyl group, a 2-methyl-1-propenyl group, a 1-methyl-2-propenyl group, a 2-methyl-2-propenyl group, a 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 1-methyl-1-butenyl group, a 2-methyl-1-butenyl group, a 3-methyl-1-butenyl group, a 2-methyl-2-butenyl group, a 3-methyl-2-butenyl group, a 2-methyl-3-butenyl group, a 1,3-butadienyl group, a 3-methyl-3-butenyl group, a 1-hexenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group, a 2-methyl-1-pentenyl group, a 3-methyl-1-pentenyl group, a 4-methyl-1-pentenyl group, a 1-heptenyl group, a 1-octenyl group, a 1-nonenyl group, a -decenyl group, a 1-undecenyl group, a 1-dodecenyl group, a 1-tridecenyl group, a 1-tetradecenyl group, a 1-pentadecenyl group, a 1-hexadecenyl group, a 1-octadecenyl group, etc. Preferably, those having 2 to 8 carbon atoms are used.
The lower alkenyl group preferably includes a straight chain or branched chain lower alkenyl group such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl. 4-hexenyl, 5-hexenyl, 1,4-methylpentenyl, etc.
The halogen atom includes fluorine, chlorine, bromine, and iodine atoms and its preferable examples are fluorine, chlorine, and bromine atoms.
The halo-lower alkyl group means the above-described lower alkyl group substituted with the above-described halogen atom, including fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, iodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 1,1-dichloroethyl, 1,1-dibromoethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2-dibromoethyl, 1,2-difluoroethyl, 1,2-dichloroethyl, 1,2-dibromoethyl, 2,2,2-trifluoroethyl, heptafluoroethyl, 1-fluoropropyl, 1-chloropropyl, 1-bromopropyl, 2-fluoropropyl, 2-chloropropyl, 2-bromopropyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 1,1-difluoropropyl, 1,1-dichloropropyl, 1,1-dibromopropyl, 1,2-difluoropropyl, 1,2-dichloropropyl, 1,2-dibromopropyl, 2,3-difluoropropyl, 2,3-dichloropropyl, 2,3-dibromopropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 2-fluorobutyl, 2-chlorobutyl, 2-bromobutyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 4-iodobutyl, 3,4-dichlorobutyl, 2,4dibromopentyl, 3,3,4,4,4-pentafluorobutyl, 2,2,3,3,4,4,4-heptafluorobutyl, perfluorobutyl, 2-fluoropentyl, 2-chloropentyl, 2-bromopentyl, 5-fluoropentyl, 5-chloropentyl, 3-iodopentyl, omopentyl, 2-fluorohexyl, 2-chlorohexyl, 2-bromohexyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 1,3,5-trifluorohexyl, perfluorohexyl, etc.
The lower alkoxy group means a straight chain or branched chain alkoxyl group having up to 6 carbon atoms, including methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, sec-butyloxy, t-butyloxy, n-pentyloxy, i-pentyloxy, sec-pentyloxy, 2,2-di-methylpropyloxy, 2-methylbutoxy, n-hexyloxy, i-hexyloxy, t-hexyloxy, sec-hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1-ethyl-butyloxy, 2-ethylbutyloxy, 1,1-dimethylbutyloxy, 2,2-dimethyl-butyloxy, 3,3dimethylbutyloxy, 1-ethyl-1-methylpropyloxy, etc.
The lower alkoxycarbonyl group means a carbonyl group to which the above-described lower alkoxyl group is bonded, including methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, i-propyloxycarbonyl, n-butyloxycarbonyl, i-butyloxycarbonyl, sec-butyloxycarbonyl, t-butyloxycarbonyl, n-pentyloxycarbonyl, i-pentyloxycarbonyl, sec-pentyloxycarbonyl, t-pentyloxycarbonyl, 2,2-dimethylpropyloxycarbonyl, 2-methylbutyloxycarbonyl, n-hexyloxycarbonyl, i-hexyloxycarbonyl, t-hexyloxycarbonyl, sec-hexyloxycarbonyl, 2-methylpentyloxycarbonyl, 3-methylpentyloxy-carbonyl, 1-ethylbutyloxycarbonyl, 2-ethylbutyloxycarbonyl, 2,2-dimethylbutyloxycarbonyl, 3,3 -dimethylbutyloxycarbonyl, 1-ethyl-1-methylpropyloxycarbonyl, etc.
The lower cycloalkyloxy-lower alkyl group means the above-described lower alkyl group having bonded thereto a cycloalkyloxy group having 3 to 7 carbon atoms, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and the like. Examples thereof include (cyclopropyloxy)methyl, 2-(cyclopropyloxy)ethyl, (cyclobutyloxy)methyl, 3-(cyclo-butyloxy)propyl, cyclopentyloxymethyl, 2-(cyclopentyloxy)ethyl, 4-(cyclopentyloxy)butyl, (cyclohexyloxy)methyl, 1-(cyclo-hexyloxy)ethyl, 2-(cyclohexyloxy)ethyl, 3-(cyclohexyloxy)propyl, 2-(cyclohexyloxy)propyl, 1-(cyclohexyloxy)propyl, 4-(cyclo-hexyloxy)butyl, 3-(cyclohexyloxy)butyl, 2-(cyclohexyloxy)butyl, 6-(cyclohexyloxy)hexyl, 1-(cyclohexyloxy)butyl, (cyclo-heptyloxy)methyl, etc.
The lower cycloalkyl-lower alkyloxy group means the above-described lower alkoxy group having bonded thereto a cycloalkyl group having 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Examples thereof include (cyclopropylmethyl)oxy, (2-cyclopropylethyl)oxy, (cyclobutylmethyl)oxy, (3-cyclobutylpropyl)oxy, (cyclopentyl-methyl)oxy, (2-cyclopentylethyl)oxy, (4-cyclopentylbutyl)oxy, (cyclohexylmethyl)oxy, (1-cyclohexylethyl)oxy, (2-cyclohexyl-ethyl)oxy, (3-cyclohexylpropyl)oxy, (2-cyclohexylpropyl)oxy, (1-cyclohexylpropyl)oxy, (4-cyclohexylbutyl)oxy, (3-cyclohexyl-butyl)oxy, (2-cyclohexylbutyl)oxy, (6-cyclohexylhexyl)oxy, (1-cyclohexylbutyl)oxy, cycloheptylmethyloxy, etc.
The lower alkylthio group means a straight chain or branched chain alkylthio group having up to 6 carbon atoms, including methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio, t-butylthio, n-pentylthio, i-pentylthio, sec-pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio, n-hexylthio, i-hexylthio, t-hexylthio, sec-hexylthio, 2-methyl-pentylthio, 3-methylpentylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1-dimethylbutylthio, 2,2-dimethylbutylthio, 3,3-dimethyl-butylthio, 1-ethyl-1-methylpropylthio, etc. Preferred are those having carbon atoms 1 to 4 such as methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio, or t-butylthio.
The lower alkanesulfinyl group means a straight chain or branched chain alkanesulfinyl group with the alkyl moiety thereof containing up to 6 carbon atoms, including methanesulfinyl, ethanesulfinyl, 1-propanesulfinyl, 2-propanesulfinyl, 1-butanesulfinyl, 2-butanesulfinyl, 1,1-dimethylethanesulfinyl, 1-(2-methylpropane)-sulfinyl, 1-pentanesulfinyl, 2-pentanesulfinyl, 3-pentanesulfinyl, 1-(3-methylbutane)sulfinyl, 1,1-dimethylpropanesulfmyl, 1-hexanesulfinyl, 2-hexanesulfinyl, 3-hexanesulfinyl, 1-(2-methyl-pentane)sulfinyl, 1-(3-methylpentane)sulfinyl, 1-(4-methyl-pentane)sulfinyl, 2-ethylbutane-1-sulfmyl, 3-ethylbutane-1-sulfinyl, 1,1-dimethylbutane-1-sulfinyl, 2,2-dimethylbutane-1-sulfinyl, 3,3-dimethylbutane-1-sulfinyl, 1-ethyl-1-methyl-propane-1-sulfinyl, etc.
The lower alkanesulfonyl group means a straight chain or branched chain alkanesulfonyl group with the aikyl moiety thereof containing up to 6 carbon atoms, including methanesulfonyl, ethanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl, 1-butanesulfonyl, 2-butanesulfinyl, 1,1-dimethylethanesulfonyl, 1-(2-methylpropane)-sulfonyl, 1-pentanesulfonyl, 2-pentanesulfonyl, 3-pentanesulfonyl, 1-(3-methylbutane)sulfonyl, 1,1-dimethylpropanesulfonyl, 1-hexanesulfonyl, 2-hexanesulfonyl, 3-hexanesulfonyl, 1-(2-methyl-pentane)sulfonyl, 1-(3-methylpentane)sulfonyl, 1-(4-methyl-pentane)sulfonyl, 2-ethylbutane-1-sulfonyl, 3-ethylbutane-1-sulfonyl, 1,1-dimethylbutane-1-sulfonyl, 2,2-dimethylbutane-1-sulfonyl, 3,3-dimethylbutane-1-sulfonyl, 1-ethyl-1-methyl-propane-1-sulfonyl, etc.
The aromatic group means an aryl or heterocyclic aromatic group. Throughout this specification, the aryl group means those having 6 to 10 carbon atoms such as phenyl, naphthyl, or the like. When simply referred to as xe2x80x9cnaphthyl groupxe2x80x9d, it includes 1-naphthyl and 2-naphthyl groups. The heterocyclic aromatic group means an unsaturated monocyclic or polycyclic heterocyclic group containing at least one hetero atom such as oxygen, sulfur, and nitrogen atoms, including pyrrolyl, imidazolyl, furyl, thienyl, thiazolyl, pyridyl, benzimidazolyl, benzofuryl, indolyl, benzothienyl, quinolyl, isoquinolyl, thiophenyl, furanyl, etc. The position of the substituted hetero atom as described above on the aromatic ring is not particularly restricted.
The halo-aromatic group means the above-described aromatic group substituted with the above-described halogen atom, including 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-iodophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-iodophenyl, 4-fluorophenyl. 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 4-bromo-2-chlorophenyl, 4-iodo-2-chlorophenyl, 1-bromonaphthalen-2-yl, 2-chloronaphthalen-1-yl, 5-chloro-naphthalen-1-yl, 6-chloro-naphthalen-1-yl, 4-chloroisoquinolin-8-yl, 2-chloroquinolin-4-yl, 4-bromoisoquinolin-1-yl, 5-chloro-thiophen-2-yl, 5-bromothiophen-2-yl and 5-chlorothiophen-3-yl, etc.
The aromatic lower alkyl group means a lower alkyl group to which the above-described aromatic group is bonded, including benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, phenylbutyl, phenyl-pentyl, phenylhexyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, pyridylmethyl, pyridylethyl, quinolylmethyl, isoquinolylmethyl, etc. The aromatic group may be substituted with a halogen atom or a group such as lower alkyl, halo-lower alkyl, nitro, lower alkoxycarbonyl, aromatic, aromatic lower alkyloxy, lower cycloalkyloxy-lower alkyl, aromatic lower alkyl, aromatic lower alkenyl, aromatic lower alkynyl, aromatic oxy-lower alkyl, lower cycloalkyl-lower alkyloxy, lower alkenyl, lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, or lower alkanesulfonylcarbamoyl.
The lower alkyl aromatic group means the above-described aromatic group to which the above-described lower alkyl group is bonded, including 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-diethylphenyl, 3,5-dimethylphenyl, 2,3,5,6-tetramethylphenyl, pentamethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-n-propylphenyl, 2-i-propylphenyl, 3-n-propylphenyl, 3-i-propylphenyl, 4-n-propylphenyl, 4-i-propylphenyl, 2,4,6-tri-i-isopropylphenyl, 2-n-butylphenyl, 2-i-butylphenyl, 2-t-butylphenyl, 3-n-butylphenyl, 3-i-butylphenyl, 3-t-butylphenyl, 4-n-butylphenyl, 4-i-butylphenyl, 4-t-butylphenyl, 4-n-pentylphenyl, 4-i-pentylphenyl, 4-t-pentylphenyl, 4-n-hexylphenyl, 2-methylnaphthalen-1-yl, 3-methylnaphthalen-1-yl, 4-methyl-naphthalen-1-yl, 5-methylnaphthalen-1-yl, 6-methylnaphthalen-1-yl, 7-methylnaphthalen-1-yl, 8-methylnaphthalen-1-yl, 1-methyl-naphthalen-2-yl, 3-methylnaphthalen-2-yl, 4-methyinaphthalen-2-yl, 5-methyinaphthalen-2-yl, 6-methylnaphthalen-2-yl, 7-methyl-naphthalen-2-yl, 8-methylnaphthalen-2-yl, 5,8-dimethyl-naphthalen-1-yl, 5,8-dimethylnaphthalen-2-yl, etc.
The aromatic oxy lower alkyl group means the above-described aromatic group to which the above-described lower alkyl group is bonded via an oxygen atom, including (phenyloxy)methyl, (1-naphthyloxy)methyl, (2-naphthyloxy)methyl, 1-(phenyloxy)ethyl, 2-(phenyloxy)ethyl, 1-(1-naphthyloxy)ethyl, 1-(2-naphthyloxy)-ethyl, 2-(1-naphthyloxy)ethyl, 2-(2-naphthyloxy)ethyl, 1-(phenyloxy)propyl, 2-(phenyloxy)propyl, 3-(phenyloxy)propyl, 1-(1-naphthyloxy)propyl, 1-(2-naphthyloxy)propyl, 2-(1-naphthyl-oxy)propyl, 2-(2-naphthyloxy)propyl, 3-(1-naphthyloxy)propyl, 3-(2-naphthyloxy)propyl, 4-(phenyloxy)butyl, 5-(phenyloxy)pentyl, 6-(phenyloxy)hexyl, etc.
The aromatic lower alkyloxy group means the above-described aromatic group to which the above-described lower alkoxyl group is bonded, including benzyloxy, 1-naphthylmethyloxy, 2-naphthyl-methyloxy, (1-phenylethyl)oxy, (2-phenylethyl)oxy, (1-naphthyl-ethan-1-yl)oxy, (2-naphthylethan-1-yl)oxy, (1-naphthylethan-2-yl)oxy, (2-naphthylethan-2-yl)oxy, (1-phenylpropyl)oxy, (2-phenylpropyl)oxy, (3-phenylpropyl)oxy, (1-naphthylpropan-1-yl)oxy, (2-naphthylpropan-1-yl)oxy, (1-naphthylpropan-2-yl)oxy, (2-naphthylpropan-2-yl)oxy, (1-naphthylpropan-3-yl)oxy, (2-naphthylpropan-3-yl)oxy, (4-phenylbutyl)oxy, (2-naphthylbutan-4-yl)oxy, (5-phenylpentyl)oxy, (2-naphthylpentan-5-yl)oxy, (6-phenythexyl)oxy, (1-naphthylhexan-6-yl)oxy, etc.
The aromatic lower alkenyl group means the above-described lower alkenyl group to which the above-described aromatic group is bonded, including 1-phenylethenyl, 2-phenylethenyl, 1-phenyl-1-propenyl, 2-phenyl-1-propenyl, 3-phenyl-1-propenyl, 1-phenyl-2-propenyl, 2-phenyl-2-propenyl, 3-phenyl-2-propenyl, 1-phenyl-1-butenyl, 2-phenyl-1-butenyl, 4-phenyl-2-butenyl, 3-phenyl-2-propenyl, 2-phenyl-1-pentenyl, 2-phenyl-3-pentenyl, 2-phenyl-1-pentenyl, 2-phenyl-1-hexenyl, etc.
The lower alkenyl aromatic group means the above-described aromatic group to which an alkenyl group having 2 to 6 carbon atoms, including 2-vinylphenyl, 3-vinylphenyl, 4-vinylphenyl, 3-iso-propenylphenyl, 4-isopropenylphenyl, 4-allyphenyl, 4-(1-butenyl)phenyl, 4-(2-butenyl)phenyl, 4-(1,3-butanedienyl)phenyl, 4-(3-butenyl)phenyl, 4-(1-pentenyl)phenyl, 5-(1-hexenyl)phenyl, etc.
The aromatic lower alkynyl group means an alkynyl group having 2 to 6 carbon atoms to which the above-described aromatic group is bonded, including phenylethynyl, 3-phenyl-1-propynyl, 3-phenyl-1-butynyl, 4-phenyl-1-butynyl, 4-phenyl-2-butynyl, 1-phenyl-2-pentynyl, 1-phenyl-4-pentynyl, 6-phenyl-1-hexynyl, etc.
Preferred salts of the benzimidazole derivatives of the present invention are non-toxic, ordinary pharmaceutically acceptable salts thereof. For example, mentioned are salts of the derivatives with bases as well as acid-addition salts of the derivatives, which include, for example, salts thereof with inorganic bases, such as salts with alkali metals (e.g., sodium, potassium); salts with alkaline earth metals (e.g., calcium, magnesium); ammonium salts; salts with organic amines (e.g., triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylene-diamine); salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid); salts with organic carboxylic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, maleic acid, tartaric acid); salts with sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid); salts with basic or acidic amino acids (e.g., arginine, aspartic acid, glutamic acid), etc.
The compounds of the invention could contain one or more chiral centers, therefore they could be enantiomers or diastereomers. Few of the compounds containing alkenyl group could also be cis- or trans- isomers. In both cases, each of such isomers as well as the mixture thereof are within the scope of this invention.
The compounds of the invention can also exist as tautomers, and individual of such tautmers and the mixture thereof are within the scope of this invention.
The compounds of the invention and their salts can be solvate, which are also within the invention. The solvent for the solvate is preferably hydrate or ethanol.
Specific examples of the compounds of the present invention include 1-(isoquinolin-3-ylmethyl)-2-methyl-6-(1-pentane-sulfonylcarbamoyl)benzimidazole, 1-((4-chloroisoquinolin-3-yl)-methyl)-2-methyl(1-pentanesulfonylcarbamoyl)benzimidazole, 1-((1-bromonaphthalen-2-yl)methyl)-2-methyl-6-(1-pentanesulfonyl-carbamoyl)benzimidazole, 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)sulfonylcarbamoyl)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)sulfonylcarbamoyl)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)sulfonylcarbamoyl)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-(((E)-1-pent-1-en)sulfonylcarbamoyl)-benzimidazole, 6-(benzenesulfonylcarbamoyl)-1-(2,4-dichloro-benzyl)-2-methylbenzimidazole, 6-(Nxe2x80x2-butanesulfonylhydrazino-carbonyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 6-((n-butylaminosulfonyl)carbamoyi)-1-(2,4-dichlorobenzyl)-2-methyl-benzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-[Nxe2x80x2-(4-methyl-phenylsulfonyl)ureido]benzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-(Nxe2x80x2-phenylureido)benzimidazole, 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-(1-pentanesulfonyl-carbamoyl)benzimidazole, 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-(((E)-1-pent-1-en)sulfonylcarbamoyl)benzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-((E)-2-phenylethenylsulfonyl-carbamoyl)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-phenyl-benzyl)-2-methyl-6-(((E)-1-pent-1-en)sulfonylcarbamoyl)-benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((4-methylbenzene)sulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2 -methyl-6-((E)-2-phenylethenylsulfonylcarbarmoyl)-benzimidazole, 1-(2-chloro-4-phenylbenzyl)-6-((5-chlorothiophen-2-yl)sulfonylcarbamoyl)-2-methylbenzimidazole, 1-(4-bromo-2-chlorobenzyl)-2-methyl-6-(((E)-1-pent-1-en)sulfonylcarbamoyl)-benzinidazole, 1-(4-bromo-2-chlorobenzyl)-2-methyl-6-((4-methyl-benzene)sulfonylcarbamoyl)benzimidazole, 1-(4-bromo-2-chloro-benzyl)-2-methyl-6-((E)-2-phenylethenylsulfonylcarbamoyl)-benzimidazole, 1-(4-bromo-2-chlorobenzyl)-6-((5-chlorothiophen-2-yl)sulfonylcarbamoyl)-2-methylbenzimidazole, 1-(4-benzyloxy-2-chlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)-benzimidazole, 1-(4-benzyloxy-2-chlorobenzyl)2-methyl-6-((4-methylbenzene)sulfonylcarbamoyl)benzimidazole, 6-((5-bromothio-phen-2-yl)sulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methyl-benzimidazole, 6-((5-bromothiophen-2-yl)sulfonylcarbamoyl)-1-(2-chloro-4-phenylbenzyl)-2-methylbenzimidazole, 1-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-methyl-6-(1-pentanesulfonyl-carbamoyl)benzimidazole, 1-(2-chloro-4-(cyclohexylmethyloxy)-benzyl)-2-methyl-6-((4-methylbenzene)sulfonylcarbamoyl)-benzimidazole, 6-((5-chlorothiophen-2-yl)sulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(4-bromo-2-chloro-benzyl)-6-((5-bromothiophen-1-yl)sulfonylcarbamoyl)-2-methyl-benzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-((4-vinyl-benzene)sulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-bromo-benzyl)-2-methyl-6-((4-vinylbenzene)sulfonylcarbamoyl)-benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((4-vinyl-benzene)sulfonylcarbamoyl)benzimidole. 1-(2,4-dichlorobenzyl)-2-methyl-6-((4-methylbenzene)sulfonylcarbamoyl)benzimidazole, (+)-1-(1-(2,4-dichlorophenyl)ethyl)-2-methyl-6-(1-pentane-sulfonylcarbamoyl)benzimidazole, (xe2x88x92)-1-(1-(2,4-dichlorophenyl)-ethyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(4-bromo-2-chlorobenzyl)-2-methyl-6-((1-pent-4-en)sulfonyl-carbarnoyl)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(((E)-1-pent-4-en)sulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-nitrobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)-benzimidazole, 1-(2-chloro-4-phenylethynylbenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)-benzimidazole, 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-methyl-6-((4-methylbenzene)sulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-(1-hexen-1-yl)benzyl)-2-methyl-6-(1-pentanesulfonyl-carbamoyl)benzimidazole, 1-(2-chloro-(1-hexen-1-yl)benzyl)-2-methyl-6-((4-methylbenzene)sulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-6-(1-pentane-sulfonylcarbamoyl)benzimidazole, 1-(4-t-butylthio-2-chloro-benzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(4-t-butylthio-2-chlorobenzyl)-2-methyl-6-((4-methylbenzene)-sulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-(phenoxymethyl)-benzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-(phenoxymethyl)benzyl)-2-methyl-6-((4-methyl-benzene)sulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-(cyclo-hexyloxymethyl)benzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)-benzimidazole, 1-(2-chloro-4-(cyclohexyloxymethyl)benzyl)-2-methyl-6-((4-methylbenzene)sulfonylcarbamoyl) benzimidazole, 1-(2-chlorphenylbenzyl)-2-methyl-6-((n-pentylaminosulfonyl)-carbamoyl)benzimidazole, 1-(2,4-chlorobenzyl)-2-methyl(((4-methylphenyl)aminosulfonyl)carbamoyl)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(((4-methylphenyl)amino-sulfonyl)carbamoyl)benzimidazole, 1-(2-chloro-4-iodobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-iodobnzyl)-2-methyl-6-((4-methylbenzene)sulfonylcarbamoyl)-benzimidazole, 1-(2-chloro-4-ethoxybenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-ethoxy-benzyl)-2-methyl-6-((4-methylbenzene)sulfonylcarbamoyl)-benzimidazole, 1-(2-chloro-4-(1-pentanesulfonylcarbamoyl)-benzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(4-bromo-2-chlorobenzyl)-2-methyl-6-(1-pentanesulfonyl-carbamoyl)benzimidazole, 1-(2-chloro-4-(trifluoromethyl)-benzyl)-2-methyl-6-(4-methylbenzene)sulfonylcarbamoyl)-benzimindazole, 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-((4-vinylbenzene)sulfonylcarbamoyl)benzimidazole, (R)-1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)sulfonylcarbamoyl)-2-methylbenzimidazole, (S)-1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)sulfonylcarbamoyl)-2-methylbenzimidazole, optically active 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)sulfonyl-carbamoyl)-2-methylbenzimidazole (showing longer retention time by liquid chromatography), optically active 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)sulfonylcarbamoyl)-2-methylbenzimidazole (showing shorter retention time by liquid chromatography), optically active 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)sulfonyl-carbamoyl)-2-methylbenzimidazole (showing longer retention time by liquid chromatography), optically active 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)sulfonylcarbamoyl)-2-methyl-benzimidazole (showing shorter retention time by liquid chromatography), 1-(2-chloro-4-(1-hexyl)benzyl)-2-methyl-((4-methylbenzene)sulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-(1-hexyl)benzyl)-2-methyl-6(pentanesulfonylcarbamoyl)-benzimidazole, 1-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-6-((4-methylbenzene)sulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-6-(1-pentanesulfonyl-carbamoyl)benzimidazole, 1-(2-chloro-4-(furan-2-yl)benzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-(furan-2-yl)benzyl)-2-methyl-6-((4-methylbenzene)sulfonyl-carbamoyl)benzimidazole, 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-((4-methylbenzene)sulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-(2-phenylethynyl)benzyl)-2-methyl-6-((E)-1-pentene-1-sulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-(phenyl-ethynyl)benzyl)-2-methyl-6-((4-vinylbenzene)sulfonylcarbamoyl)-benzimidazole, 1-(2-chloro-4-phenylethynyl)benzyl)-2-methyl-6-((E)-2-phenylethenylsulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-6-((4-vinylbenzene)-sulfonylcarbamoyl)-2-methylbenzimidazole, 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-6-((E)-1-pentene-1-sulfonylcarbamoyl)-2-methylbenzimidazole, 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-methyl-6-((E)-2-phenylethenylsulfonylcarbamoyl) benzimidazole, 1-(4-butyloxy-2-chlorobenzyl)-6-(1-pentanesulfonylcarbamoyl)-2-methylbenzimidazole, 1-(2-chloro-4-(3-methylbutoxy)benzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(2-chloro-4-(3-methylbutoxy)benzyl)-2-methyl-6-((4-methylbenzene)sulfonyl-carbamoyl)benzimidazole, etc.
The benzimidazole derivatives and their pharmaceutically acceptable salts of the present invention that are mentioned hereinabove are effective for preventing and treating various disorders, for example, impaired glucose tolerance, diabetes (type II diabetes), diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dernatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc.), syndrome of insulin resistance (e.g., insulin receptor disorders, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly, etc.), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.), hyperglycemia (e.g., abnormal saccharometabolism such as feeding disorders, etc.), and hypertension based on their blood sugar level-depressing activity, as well as stenocardia, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis etc.), tubulointerstitial disorders (e.g., renopathy induced by FK506, cyclosporin, etc.), renal failure, atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chronic reversible obstructions (e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.), autoimmune diseases, allergic rhinitis, urticaria, glaucoma, diseases characterized by enteromotility disorders (e.g., hypersensitive enteropathy syndrome, etc.), impotence (e.g., organic impotence, psychic impotence, etc.), and diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc.), nephritis, cachexia (e.g., progressive weight loss dLe to the lipolysis, myolysis, anemia, edema, anorexia, etc. associated with chronic diseases such as cancer, tuberculosis, endocrine disorder, AIDS, etc.), pancreatitis, and restenosis after PTCA based on their cGMP-PDE (especially PDE-V)-inhibiting activity, smooth muscle relaxing activity, bronchodilating activity, vasodilating activity, smooth muscle cell suppressing activity, and antiallergic activity.
To use the benzimidazole derivatives of the present invention for treating diseases or disorders such as those mentioned hereinabove, they may be formulated into pharmaceutical compositions of ordinary forms, which comprise, as an active ingredient, any of the derivatives along with pharmaceutically acceptable carriers, such as organic or inorganic solid or liquid vehicles, and which are suitable for oral administration, parenteral administration or external application. The pharmaceutical compositions may be of any solid form of tablets, granules, powders, capsules, etc., or may be of any liquid form of solutions, suspensions, syrups, emulsions, lemonades, etc.
If desired, the pharmaceutical compositions may further contain a pharmaceutical aid, a stabilizer, a wetting agent, and also any ordinary additive of, for example, lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, etc.
The amount of the above-mentioned derivative of the present invention to be used shall vary, depending on the age and the condition of patients, the type and the condition of diseases or disorders, and the type of the derivative to be used. In general, for oral administration, the dose of the derivative may be from 1 to 100 mg/kg; and for intramuscular injection or intravenous injection, it may be from 0.1 to 10 mg/kg. Such a unit dose may be applied to a patient once to four times a day.